EP1090917B1

EP1090917B1 - Quinolin-4-yl derivatives and their use as NMDA-receptor subtype blockers

Info

Publication number: EP1090917B1
Application number: EP00121561A
Authority: EP
Inventors: Alexander Alanine; Serge Burner; Bernd Buettelmann; Marie-Paule Heitz Neidhart; Georg Jaeschke; Emmanuel Pinard; René Wyler
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1999-10-08
Filing date: 2000-10-02
Publication date: 2005-12-21
Anticipated expiration: 2020-10-02
Also published as: HRP20000652A2; TR200002893A2; DE60024947D1; KR20010050915A; DE60024947T2; ZA200005447B; CA2322309C; NO20005031L; BR0004709A; CA2322309A1; PE20010660A1; AR032601A1; MA26753A1; PL343057A1; JP3385318B2; EP1090917A1; DK1090917T3; US6339093B1; IL138916A0; KR100398562B1

Description

The present invention relates to compounds of the general formula
wherein

R¹: is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, nitro, cyano, lower alkyl-amino, di-lower alkyl-amino or halogen;
R²: is hydrogen, lower alkyl, amino, pyrrolidin-3-ol, pyrrolidin-2-yl-methanol or -NHCH₂CHROH;
R³: is hydrogen or halogen;
R: is hydrogen, lower alkyl or -CH₂OH;
n: is 1 or 2;

The compounds of formula I and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
The compounds of the present invention are novel. WO 97/23458 describes, inter alia, tetrahydroisoquinoline derivatives with a very broad substitution in 1-position, which compound are subtype-selective NMDA receptor ligands.
Furthermore, J. Med. Chem 1997, 40, 754-765 describes 3- and 4-substituted quinolin-2-ones with antagonistic activity at the glycine site on the NMDA receptor. Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, chronic and acute pain.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the manufacture of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, and, respectively, for the manufacture of corresponding medicaments.
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term "lower alkyl" denotes a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
The term "halogen" denotes chlorine, iodine, fluorine and bromine.
The term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above.
The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I in the scope of the present invention are those, wherein n is 2 and R¹ and R³ are hydrogen. These are the following compounds:
(RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol,
(S)-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propan-2-ol,
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamine and
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline.
Compounds of the present invention, in which n is 1, R¹ is hydrogen and R³ is hydrogen or halogen, are further preferred, for example the following compounds:
4-(5-chloro-1,3-dihydro-isoindol-2-yl)-quinoline and
4-(1,3-dihydro-isoindol-2-yl)-quinoline.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a compound of formula
with an amine of formula
to a compound of formula
wherein R¹ - R³ and n have the significances given above, or
or
b) reacting a compound of formula
with a compound of formula HR² wherein R¹ to R³ and n have the significances given above with the exception that R² is not hydrogen, lower alkyl or amino, to give a compound of formula I, and
if desired, modifying one or more substituents within the definitions given above, or
if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
In the following the preparation of compounds of formula I are described in more detail:
In accordance with the process variants, described above, and with the scheme 1, described below, compounds of formula I may be prepared by known procedures, for example the following

by reaction at 150-160°C of a 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl) or a 2-chloro-4-(1,3-dihydro-isoindol-2-yl)-quinoline with a primary or secondary amine using the neat amine as solvent, or
by reaction at 140-150°C of a 4-chloro-quinoline with a 1,2,3,4-tetrahydroisoquinoline or a 2,3-dihydro-1H-isoindole in a stoechiometric fashion.

2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines and 2-chloro-4-(1,3-dihydro-isoindol-2-yl)-quinolines were prepared using known methods (Curd, F. H. S.; Raison, C. G.; Rose, F. L.; J. Chem. Soc. 1947, 899) by reacting a 2,4-dihydroxy-quinoline with a 1,2,3,4-tetrahydroisoquinoline or a 2,3-dihydro-1H-isoindole at 200°C followed by a treatment with a chlorinating agent like phosphorus oxychloride.
4-Chloro-quinolines were prepared using known methods by reacting the corresponding quinolin-4-ones with a chlorinating agent like phosphorus oxychloride (scheme 1)
Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.
In scheme 1 are described processes for preparation of compounds of formula I, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner.
The preparation of compounds of formula I are described in more detail in working examples 1-18.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable acid addition salts possess valuable pharmacodynamic properties. They are NMDA-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
The compounds were investigated in accordance with the test given hereinafter.

Test method

³ H-Ro 25-6981 binding (Ro 25-6981 is [R-(R*,S*)]-a-(4-Hydroxy-phenyl)-b-methyl-4-(phenyl-methyl)-1-piperidine propanol)

Male Füllinsdorf albino rats weighing between 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with a Polytron (10.000 rpm, 30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH 7.1 buffer. The homogenate was centrifuged at 48,000 g for 10 minutes at 4°C. The pellet was resuspended using the Polytron in the same volume of buffer and the homogenate was incubated at 37°C for 10 minutes. After centrifugation the pellet was homogenized in the same buffer and frozen at -80°C for at least 16 hours but not more than 10 days. For the binding assay the homogenate was thawed at 37°C, centrifuged and the pellet was washed three times as above in a Tris-HCl 5 mM, pH 7.4 cold buffer. The final pellet was resuspended in the same buffer and used at a final concentration of 200 mg of protein/ml.
³H-Ro 25-6981 binding experiments were performed using a Tris-HCl 50 mM, pH 7.4 buffer. For displacement experiments 5 nM of 3H-Ro 25-6981 were used and non specific binding was measured using 10 mM of tetrahydroisoquinoline and usually it accounts for 10% of the total. The incubation time was 2 hours at 4°C and the assay was stopped by filtration on Whatmann GF/B glass fiber filters (Unifilter-96, Packard, Zürich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted on a Packard Top-count microplate scintillation counter after addition of 40 mL of microscint 40 (Canberra Packard S.A., Zürich, Switzerland).
The effects of compounds were measured using a minimum of 8 concentrations and repeated at least once. The pooled normalized values were analyzed using a non-linear regression calculation program which provide IC₅₀ with their relative upper and lower 95% confidence limits.
The IC₅₀(µM) of preferred compounds of formula I, tested in accordance with the above mentioned methods, is <1µM.
Examples of some IC₅₀ values are given in the table below:

Example IC ₅₀ (µM)

2 0.058

4 0.17

5 0.29

13 0.19

15 0.32

16 0.65

18 0.89
The compounds of formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of general formula I although the upper limit can also be exceeded when this is shown to be indicated.
The following examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degree Celsius.

Example 1

(RS)-3-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol hydrochloride

2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.44 g, 1.5 mmol) and (RS)-3-amino-1,2-propanediol (0.82 g, 9.0 mmol) were mixed and heated at 150-160°C for 5 hours. The reaction mixture was cooled to room temperature and water (15 ml) was added. The resulting solid was filtrated, dried and chromatographed over silica gel (CH₂Cl₂-MeOH, 19:1 then 9:1) to provide a white foam which was dissolved in MeOH. HCl-Et₂O was added to provide (RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol hydrochloride (0.4 g, 69 %) as an offwhite foam, MS: m/e = 349 (M⁺).
Following the general method of example 1 the compounds of example 2 to example 5 were prepared.

Example 2

2-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-ethanol hydrochloride

The title compound, MS: m/e = 320.3 (M+H⁺), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and ethanolamine.

Example 3

(S)-1-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propan-2-ol hydrochloride

The title compound, MS: m/e = 334.3 (M+H⁺), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and S(+)-1-amino-2-propanol.

Example 4

(R)-1-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-yl]-pyrrolidin-3-ol hydrochloride

The title compound, m.p. 270-274°C, [α] 20 / D = -34° (c = 0.54, methanol) and MS: m/e = 346.3 (M+H⁺), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and (R)-3-hydroxypyrrolidine.

Example 5

(R)-{1-[4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-yl]-pyrrolidin-2-yl}-methanol

The title compound, m.p. 74-80 °C, [α] 20 / D = +63.2° (c = 0.53, methanol) and MS: m/e = 360.3 (M+H⁺), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and D-prolinol.

Example 6

4-(5-Chloro-1,3-dihydro-isoindol-2-yl)-quinoline hydrochloride

A mixture of 4-chloroquinoline (0.245 g,1.5 mmol) and 5-Chloro-2,3-dihydro-1H-isoindole (0.23 g, 1.5 mmol) was heated at 140-150°C for 4 hours under Argon then cooled to room temperature.The crude product was recrystallized with methanol to provide 4-(5-Chloro-1,3-dihydro-isoindol-2-yl)-quinoline hydrochloride (0.115 g, 24%) as white solid, m.p. 270-275°C and MS: m/e = 280 (M⁺).
5-Chloro-2,3-dihydro-1H-isoindole is a known compound and has been prepared as described in the following reference: EP 343560
Following the general method of Example 6 the compounds of Example 7 to Example 18 were prepared.

Example 7

4-(1,3-Dihydro-isoindol-2-yl)-quinoline hydrochloride

The title compound, m.p. 264-267°C and MS: m/e = 247.3 (M+H⁺), was prepared from 4-chloroquinoline and 2,3-dihydro-1H-isoindole.

Example 8

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamine

The title compound, MS: m/e = 276.3 (M+H⁺), was prepared from 4-chloroquinolin-2-ylamine and 1,2,3,4-tetrahydroisoquinoline.

Example 9

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinoline hydrochloride

The title compound, m.p. 200°C, and MS: m/e = 260 (M⁺), was prepared from 4-chloro-quinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 10

The title compound, m.p. 218-219°C, and MS: m/e = 291.2 (M+H⁺), was prepared from 4-chloro-6-methoxy-quinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 11

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-7-methoxy-quinoline hydrochloride

The title compound, MS: m/e = 291.2 (M+H⁺), was prepared from 4-chloro-7-methoxy-quinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 12

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-8-methoxy-quinoline hydrochloride

The title compound, m. p. 240 °C MS: m/e = 291.2 (M+H⁺), was prepared from 4-chloro-8-methoxy-quinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 13

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-7-methyl-quinoline hydrochloride

The title compound, m. p. 251-252 °C MS: m/e = 275.3 (M+H⁺), was prepared from 4-chloro-7-methyl-quinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 14

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-methyl-quinoline hydrochloride

The title compound, m. p. 210-211 °C MS: m/e = 275.3 (M+H⁺), was prepared from 4-chloroquinaldine and 1,2,3,4-tetrahydroisoquinoline.

Example 15

7-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline hydrochloride

The title compound, MS: m/e = 295.3 (M+H⁺), was prepared from 4,7-dichloroquinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 16

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-8-fluoro-quinoline hydrochloride

The title compound, MS: m/e = 279.2 (M+H⁺), was prepared from 4-chloro-8-fluoroquinoline and 1,2,3,4-tetrahydroisoquinoline.

Example 17

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-quinolin-6-ol hydrochloride

The title compound, MS: m/e = 277.2 (M+H⁺), was prepared 4-chloro-quinolin-6-ol and 1,2,3,4-tetrahydroisoquinoline.

Example 18

4-(3,4-Dihydro-1H-isoquinolin-2-yl)-6-fluoro-quinoline hydrochloride

The title compound, MS: m/e = 279.2 (M+H⁺), was prepared 4-chloro-6-fluoroquinoline and 1,2,3,4-tetrahydroisoquinoline.

Example A

Tablet Formulation (Wet Granulation)
Item	Ingredients	mg/tablet
		5 mg	25 mg	100mg	500mg
1.	Compound of formula 1	5	25	100	500
2.	Lactose Anhydrous DTG	125	105	30	150
3.	Sta-Rx 1500	6	6	6	30
4.	Microcrystalline Cellulose	30	30	30	150
5.	Magnesium Stearate	1	1	1	1
	Total	167	167	167	835

Manufacturing Procedure

1 Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granulation at 50°C.
3. Pass the granulation through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.

Example B

Capsule Formulation
Item	Ingredients	mg/capsule
		5 mg	25mg	100mg	500mg
1.	Compound of formula	1 5	25	100	500
2.	Hydrous Lactose	159	123	148	---
3.	Corn Starch	25	35	40	70
4.	Talc	10	15	10	25
5.	Magnesium Stearate	1	2	2	5
Total	200	200	300	600

Manufacturing Procedure

1 Mix items 1, 2, and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
4. Add item 5 and mix for three minutes; compress on a suitable press.

Claims

Compounds of formula
wherein

R¹

is hydrogen, C_1-4-alkyl, C_1-4-alkoxy, ydroxyl, amino, nitro, cyano, C_1-4-alkyl-amino, di-C_1-4- alkyl-amino or halogen;

R²

is hydrogen, C_1-4-alkyl, amino, pyrrolidin-3-ol, pyrrolidin-2-yl-methanol or -NHCH₂CHROH;

R³

is hydrogen or halogen;

R

is hydrogen, C_1-4-alkyl or -CH₂OH;

n

is 1 or 2;

and pharmaceutically acceptable acid addition salts thereof.
Compounds of formula I according to claim 1, wherein n is 2 and R¹ and R³ are hydrogen.
Compounds of formula I according to claim 2, which are
(RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol,
(S)-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propan-2-ol,
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamine and
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline.
Compounds of formula I according to claim 1, wherein n is 1 and R¹ is hydrogen and R³ is hydrogen or halogen.
Compounds of formula I according to claim 4, which are
4-(5-chloro-1,3-dihydro-isoindol-2-yl)-quinoline and
4-(1,3-dihydro-isoindol-2-yl)-quinoline.
A medicament containing one or more compounds of formula I of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and an inert carrier for the treatment of diseases.
A medicament according to claim 6 for the treatment of diseases based on therapeutic indications for NMDA receptor subtype specific blockers, which include acute forms of neurodegeneration caused, by stroke and brain trauma, and chronic forms of neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and chronic or acute pain.
A process for preparing a compound of formula I as defined in claim 1, which process comprises

a) reacting a compound of formula
with an amine of formula
to a compound of formula
wherein R¹ - R³ and n have the significances given in claim 1,
or

b) reacting a compound of formula
with a compound of formula HR² wherein R¹ to R³ and n are as described in claim 1 with the exception that R² is not hydrogen, C_1-4-alkyl or amino,
to give a compound of formula I, and
if desired, modifying one or more substituents within the definitions given above, or
if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
The use of a compound of formula I in accordance with claim 1 for the manufacture of a medicament for the treatment of diseases based on therapeutic indications for NMDA receptor subtype specific blockers, which include acute forms of neurodegeneration caused by stroke and brain trauma, and chronic forms of neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and chronic or acute pain.